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Home , Aspergillosis, Cryptococcus neoformans, Pneumocystis jirovecii, Pneumocystis pneumonia, Talaromycosis

PERSPECTIVE Mem Inst Oswaldo Cruz, Rio de Janeiro, Vol. 115: e200430, 2020 1|9

Invasive fungal disease in humans: are we aware of the real impact?

Carolina Firacative1/+

1Universidad del Rosario, School of Medicine and Health Sciences, Studies in Translational Microbiology and Emerging Diseases (MICROS) Research Group, Bogota, Colombia

Despite the medical advances and interventions to improve the quality of life of those in intensive care, people with or severely immunocompromised or other susceptible hosts, invasive fungal diseases (IFD) remain severe and underappreciated causes of illness and death worldwide. Therefore, IFD continue to be a public health threat and a major hindrance to the success of otherwise life-saving treatments and procedures. Globally, hundreds of thousands of people are affected every year with , fumigatus, neoformans, , endemic dimorphic fungi and Mucormycetes, the most common fungal causing invasive diseases in humans. These result in morbidity and mortality rates that are unacceptable and represent a considerable socioeconomic burden. Raising the general awareness of the significance and impact of IFD in human health, in both the hospital and the community, is hence critical to understand the scale of the problem and to raise interest to help fighting these devastating diseases.

Key words: fungi - immunocompromised host - invasive fungal disease - risk factors

It is estimated that the fungal kingdom has six million of fungi in their natural habitat, are also important ele- species widely distributed in the environment.(1) Among ments that influence on the incidence and prevalence of these, several hundred species of both and fungal disease across the world.(6) can affect humans in several ways. The direct ingestion In this perspective article, the main risk factors of of poisonous mushrooms causes mycetismus, which can people to develop IFD are summarised, to aid recognis- result in gastrointestinal tract disorders or even death. In ing the impact of fungi on human health, an issue often cases of mycotoxicosis, humans can be also poisoned by underestimated and underappreciated. Considering that the ingestion of food contaminated with fungal toxins IFD are often disregarded during routine hospital care, (mycotoxins), which affect the , kidneys and other it is very important to emphasise to microbiologists, di- vital organs.(2) Lastly, causing , fungi can be ei- agnostic laboratory staff and clinicians, that not only the ther primary or opportunistic of humans and number but the diversity of patients at-risk for IFD are the disease is called . Ranging from superficial continuously rising, with mortality rates than remain un- infections of the , skin, nails or mucosal surfaces, acceptably high.(3) Additionally, most fungal infections which are usually benign, and other ailments includ- are not reportable diseases, thus reliable information on ing , fungi can also cause invasive infections local and global prevalence is not available. This review of internal organs that are progressive and lethal if not recalls the updated definition of IFD, collates recent epi- diagnosed and specifically treated.(3,4) To cause invasive demiological data and describes, in order of frequency, disease in humans, however, fungi must meet four crite- the most susceptible groups of people to acquire an ria: (i) the ability to grow at or above mammalian body IFD, namely those who undergo medical interventions, temperature; (ii) the ability to reach internal tissues by people with induced either by the penetrating or evading host barriers; (iii) the ability to treatment of an associated illnesses or by an underlying lyse tissues and absorb their components; and (iv) the disease, people with bacterial or viral co-infections and ability to evade host immune defences.(5) As warm- immunocompetent individuals who acquire an IFD by blooded with a highly sophisticated immune environmental exposure. system, humans are naturally resistant to most invasive Invasive fungal diseases fungal diseases (IFD). As such, most cases of invasive disease occur in patients with an underlying serious ill- According to standard criteria, an invasive or sys- ness or condition. Moreover, advances in medical care temic fungal disease is proven when tissue damage due and life-saving treatments, which may lead to an im- to fungal elements is observed by histopathologic ex- paired immune function, have increased the number of amination and/or when the aetiologic agent is isolated susceptible patients or people at-risk for fungal infec- by culture from clinical sterile samples such as blood, tions.(5) Lastly, socioeconomic and geoecological char- tissue or cerebrospinal fluid.(7) Infection can be initiated acteristics, including the exposure to a high inoculum by invasion of fungal microbiota into the mucosa, by the inhalation of fungal spores from the environment or by direct inoculation, which lead to colonisation and dis- semination. As clinical manifestations of IFD are not doi: 10.1590/0074-02760200430 specific and the severity of the disease depends on the + Corresponding author: [email protected]  https://orcid.org/0000-0001-7547-5172 host’s defences and immune response, a high degree of Received 21 August 2020 suspicion is needed for the early diagnosis and optimal Accepted 24 September 2020 management of these infections.(8)

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IFD are an emerging problem worldwide, are gener- a physical barrier intrinsically resistant to the host im- ally very difficult to cure and the associated mortality re- mune system and other environmental perturbations.(14) mains very high depending on the and patient The formation of biofilms additionally leads to upregu- population. Recent studies have estimated that globally, lation of -resistance mechanisms, as well as fungal infections kill more than 1.5 million people per the development of complex regulatory processes that year, which is similar to the mortality due to favour even higher levels of antifungal resistance, most and about three-times more than malaria.(6) However, the notably to azoles and polyenes.(15) Directly related with true burden of IFD is probably miscalculated because of medical interventions, nosocomial candidaemia is as- the absence or availability of reliable, sensitive and uni- sociated with prolonged stays in hospital and intensive versal diagnostic methods and because fungal infections care units, parenteral nutrition, as well as with improved are usually hindered by other diseases. Furthermore, survival of premature infants.(11) Despite the broad use when cases of fungal diseases are identified by a health of antifungal prophylaxis, mostly , which provider, hospital or laboratory, they are not mandatory has shown to reduce the incidence of invasive candidia- to be reported to public health departments; hence, most sis in patients who are at highest risk, almost 750,000 countries lack surveillance systems for IFD. cases of this mycosis are estimated to occur yearly in Among at-risk and immunocompromised patients, the world.(6,12) Although C. albicans is the global leading Candida albicans, , Cryptococcus agent of candidaemia and other forms of invasive candi- neoformans, Pneumocystis jirovecii, endemic dimorphic diasis, accounting for about half the amount of cases, the fungi and Mucormycetes remain the main fungal patho- frequency of non-albicans species, mainly C. glabrata, gens responsible for most cases of serious fungal diseases C. parapsilosis, C. tropicalis and C. krusei is increasing, in the world (Tables I, II, Figure).(5,6,9,10) While the ability which is of concern when selecting empiric antifungal of these fungi to cause disease depends on their virulence therapy, as non-albicans species have reduced suscepti- factors and pathogenic capacity, as well as on the interac- bility or are intrinsically resistance to azoles.(11) tions with the host and adaptation to different environ- Much less frequently, in both immunocompetent ments, the outcome of the infections is influenced by and immunocompromised individuals, fungi, includ- various others factors. The patients’ underlying medical ing Candida spp., can be directly inoculated through condition, the time for diagnosis, the choice of therapy, neurosurgical procedures and contaminated devices or especially when fighting strains or species that are resis- drug preparations. An unprecedented outbreak of fungal tant to antifungal drugs, the capacity to achieve prompt , for instance, was associated with parenteral and effective source control, and the adverse effects of injections of contaminated with A. fu- antifungal drugs alone or concomitantly administered migatus and Exserohilum rostratum, both environmen- with other drugs, are factors that significantly contribute tal molds.(16,17) Another saprophyte , Sarocladium to IFD prognosis.(5) Thus, identifying susceptible patients kiliense, was isolated from several fungaemia cases as- or those who are clinically suspected of having a fungal sociated with the administration of contaminated antin- infection, along with an early empiric therapy or prophy- ausea among oncology patients.(18,19) laxis, are of paramount importance to decrease mortality Treatment-induced immunosuppression and morbidity associated to IFD. Haematological malignancies, mainly acute leukae- Medical interventions mia, account for most cases of IFD among patients immu- The placement of central venous catheters and intra- nosuppressed in the classical sense. Prolonged severe neu- vascular or intracranial devices plus the use of broad- tropenia, resulting from intense regimens spectrum antibiotics, which are associated with medi- and defined as more than 10 days with a peripheral blood cal interventions, are responsible for the vast majority absolute count less than 500/µL, is still the sin- of IFD acquired in hospital settings. Candidaemia, the gle major risk factor for invasive infection caused by the most frequent life-threatening mycosis in the world, ap- environmental mold A. fumigatus (B in Figure) (> 80% pears among the four most common causes of health of cases) and other species of Aspergillus.(9,20) care-associated bloodstream infections (BSI), with about are known to be the primary host defence mechanism 80% of cases occurring in the absence of evident immu- against Aspergillus infection, which commonly starts by nosuppression but rather among patients with common the inhalation into and establishment of fungal spores in iatrogenic and/or nosocomial conditions.(11,12) Medical the lower . When mucosal barriers have devices disrupt the normal skin barriers and provide been injured, neutrophils function in the innate immune direct access for the commensal yeasts of the response through the killing of conidia and hyphae by Candida to the body’s interior. In addition, it has been both oxidative and nonoxidative mechanisms.(21,22) In long recognised that antibiotics suppress the growth of neutropenic patients, therefore, neutrophil dysfunction normal bacterial microbiota, which favours the prolif- represents an impairment to efficiently recruit and kill eration of Candida species, thus leading to colonisation Aspergillus infectious elements. Worldwide, it is estimat- and an increased risk of disseminated .(12,13) ed that invasive affects annually more than C. albicans (A in Figure) and other Candida species also 300,000 patients from almost 10 million at risk.(6) Despite have the ability to form biofilms on indwelling venous the availability of highly active antifungal treatment and and bladder catheters, heart valves, joint replacements the implementation of prevention strategies such as the and even on different tissues in the host. Biofilms are introduction of mold-active prophylaxis and the reduction Mem Inst Oswaldo Cruz, Rio de Janeiro, Vol. 115, 2020 3|9

TABLE I Major risk factors associated with the acquisition of an invasive fungal disease

Risk factor Specific conditions Most common pathogens

Catheters, intravascular or intracranial devices Candida albicans, Candida spp. Broad-spectrum antibiotics use C. albicans, Candida spp. Medical intervention Neurosurgical procedures, Candida spp., saprophyte fungi contaminated devices and drug preparations Severe prolonged Aspergillus fumigatus, Aspergillus spp. C. albicans, Candida spp., A. fumigatus, Solid Treatment-induced A. fumigatus, C. albicans, Candida spp., immunosuppression Haematopoietic stem cell transplantation Pneumocystis jirovecii, Mucormycetes Candida spp., Aspergillus spp., Cryptococcus spp., Biological agents P. jirovecii, dimorphic fungi, Mucormycetes P. jirovecii, C. neoformans, HIV infection Disease-induced , immunosuppression Uncontrolled diabetes , Mucormycetes Chronic obstructive pulmonary disease A. fumigatus A. fumigatus, , H. capsulatum, Tuberculosis C. neoformans, C. albicans Co-infection P. jirovecii, Aspergillus spp., Cytomegalovirus non-Aspergillus molds SARS-CoV-2 infection A. fumigatus Environmental exposure Trauma R. oryzae, Mucormycetes

HIV: human virus; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2. of exposure to Aspergillus spores, invasive aspergillosis Cytopaenia and administration of therapies to pre- in haemato-oncological patients is still associated with vent and treat graft-versus-host disease (GvHD), which extremely high mortality rates (60-70%).(23,24) leads to an impaired cell immunity, are major risk factors Similarly, thousands of solid organ transplant (SOT) of haematopoietic stem cell transplant (HSCT) recipi- recipients in the world are at risk of IFD as a result of ents for acquiring IFD.(29,30) Due to induced neutropenia organ damage, neutropenia, administration of immu- and lack of adequate immune reconstitution, invasive nosuppressive drugs and surgical factors such as pro- aspergillosis has been noted to be the most commonly longed operation time, increased technical complexity observed IFD in HSCT recipients, followed by invasive and bleeding complications. In these patients, Candida candidiasis, Pneumocystis , spp., A. fumigatus and C. neoformans (C in Figure) are (caused by Mucormycetes) and infections caused by oth- reported as the most common fungal pathogens causing er molds such as and Scedosporium species. invasive disease, although the incidence of other molds, (31,32) Gastrointestinal tract mucositis, defined as the dis- such as Fusarium spp. and dimorphic fungi, is increas- ruption of the gastrointestinal tract mucosa, together with ing.(25,26) In SOT recipients, however, the risk for and dis- the presence of venous catheters in patients who require tribution of IFD depend on the organ transplanted. It has transfusion support, allow for gut and skin microbiota, been reported that transplant recipients had the including Candida spp., to invade and cause BSI.(30,32) As lowest overall risk of IFD and lung transplant recipients in SOT recipients, IFD attributable mortality rates differ are more commonly affected by Aspergillus spp.(26,27) depending on the aetiological agent causing the infection, Survival of transplanted patients who developed an IFD with non-Aspergillus mycosis and mucormycosis being also differs depending on the aetiological agent causing responsible for most fatal cases in stem cell transplanted the infection, with candidaemia and other forms of inva- patients.(31,33) Donor type, GvHD grade, conditioning reg- sive candidiasis generally accounting for higher number imens, supportive care strategies and therapy timing are of deaths.(25,26) While is generally an factors that also influence the risk for IFD in HSCT re- early complication of SOT, aspergillosis, cryptococco- cipients.(30) Clearly, invasive mycoses hamper the success sis and other fungal infections tend to present later after of the transplantation and continue to be major threats to transplantation. In addition, time to onset of IFD may patients undergoing SOT and HSCT. also differ based on antifungal prophylaxis, site of infec- Biologic agents, such as antagonists of the tumour tion or transplant type.(28) necrosis factor (TNF)-α, which are used as therapeutic 4|9 Carolina Firacative

TABLE II Estimated incidence and mortality rates of the most frequent invasive fungal diseases affecting humans

Mycosis Main aetiologic agent Cases per year Mortality rate (%) Invasive candidiasis Candida albicans ~ 750,000(6) ~ 40(74) Invasive aspergillosis Aspergillus fumigatus > 300,000(6) 30-70(23,24) Pneumocystis jirovecii > 400,000(10) 10-60(38) Cryptococcal meningitis Cryptococcus neoformans ~ 225,000(44) 15 -50(74) Disseminated Histoplasma capsulatum ~ 100,000(6) 10 -60(42) Mucormycosis Rhizopus oryzae > 10,000(6) 35-100(49)

Photomicrographs of the most common fungal pathogens causing invasive diseases in humans. A: Candida albicans in its -phase; B: filamentous conidiophores of Aspergillus fumigatus; C: encapsulated yeasts of Cryptococcus neoformans; D: Pneumocystis jirovecii ; E: Histoplasma capsulatum in its yeast phase; F: reproductive sporangia of Rhizopus oryzae. Images are not copyrighted and were obtained from the public domain of the Public Health Image Library (PHIL) from the Centers for Disease Control and Prevention (CDC) (phil.cdc.gov).(73)

approaches for autoimmune conditions including rheu- that ranged between 5.1 to 13.3 cases per 100,000 per- matoid arthritis, juvenile idiopathic arthritis, psoriatic sons treated, over a 4.75-year period.(36) Other studies, arthritis, ankylosing spondylitis, plaque psoriasis and however, reported P. jirovecii, a unculturable yeast-like inflammatory bowel diseases directly or indirectly im- , as the most common nonviral opportunistic in- pact the immune response against fungal pathogens, fection, with 16 cases among 33,324 users of TNF-α in- mainly by affecting inflammatory processes, thus in- hibitors.(37) More rarely, agents of mucormycosis, other creasing the risk of IFD.(34,35) The immune response dimorphic fungi and non-Aspergillus molds have been against fungal pathogens can be impaired by the block- reported in patients on active biologic therapy.(34) ade of TNF-α, which leads to reduced cytokine produc- Disease-induced immunosuppression tion, impairment of monocyte recruitment, prevention of granuloma formation and apoptotic and nonapoptotic Defects in cell-mediated immunity, mainly a de- death of cells expressing TNF receptors.(34) Although crease in the number and function of CD4+ lympho- baseline predisposition of patients for fungal infections cytes, which occurs in people infected with the human due to the autoimmune disorders, concomitant immuno- immunodeficiency virus (HIV), is the major risk fac- suppressive therapies and geographical location need to tor for Pneumocystis pneumonia. Among people living be considered, Aspergillus, Candida and Cryptococcus with HIV, P. jirovecii (D in Figure) persists as the most infections are generally associated with the use TNF-α common cause of serious and often fatal respiratory inhibitors. A study reported that among people receiv- infection, that continues to be a life-threatening defin- ing these biologic agents, candidiasis was the most fre- ing illness in patients with acquired immunodeficiency quent mycosis followed by histoplasmosis, aspergillosis, syndrome (AIDS).(38) Yearly, more than 400,000 cases of and , with incidences Pneumocystis pneumonia are estimated to occur world- Mem Inst Oswaldo Cruz, Rio de Janeiro, Vol. 115, 2020 5|9 wide, with mortality rates ranging from 10-60% or high- didiasis and aspergillosis.(49,50) Mucormycetes species are er, depending on the patient population, comorbidities vasotropic and cause tissue infarctions.(49) Among them, and time for diagnosis.(10,38) Unlike other fungal species Rhizopus oryzae (F in Figure) is the most frequently re- affecting humans, evidence suggests that P. jirovecii covered species in patients with mucormycosis ( 70%), colonises the respiratory tract of asymptomatic individ- followed by Mucor spp., Rhizomucor spp., Syncephalas- uals and that person-to-person transmission is the most trum spp., Cunninghamella bertholletiae, Apophysomy∼ - likely mode of infection, which is of clinical significance ces elegans, Lichtheimia spp., and Saksenaea spp., among as colonised individuals may be at risk of development other numerous species.(51) After inhalation of spores pneumonia or may transmit Pneumocystis to others.(38,39) from environmental sources, immunocompromised Low CD4+ counts is also the most important risk hosts can develop upper and lower , factor to acquire infection by C. neoformans, an envi- which if left untreated, can subsequently spread to the ronmental encapsulated yeast.(40) As C. neoformans has CNS causing rhinocerebral mucormycosis.(52) In people a special predilection for the central nervous system with diabetes, monocytes and macrophages are dysfunc- (CNS), the main presentation of cryptococcosis is me- tional and fail to and kill the Mucormycetes ningoencephalitis, which if left untreated, is deadly or spores, allowing their germination and subsequent prolif- leads to long-term neurological sequelae.(5,41) Although eration as hyphal elements, which leads to rapid invasion the introduction of antiretroviral treatments (ART) for of deeper tissues and dissemination.(53) Despite several people living with HIV has reduced the global incidence simultaneous approaches used for treatment, such as ag- of cryptococcosis, the limited access to healthcare and gressive debridement or amputation, antifungal therapy the increasing number of HIV-positive people contribute and medical management or correction of the underly- to the high prevalence of cryptococcal infection in low- ing condition, mucormycosis associated mortality rates and middle-income countries.(42) In patients with a CD4+ continue to be very high, reaching almost 100% among count less than 100 cells/μL who are not receiving effec- patients with disseminated disease.(49,52) tive ART, screening for asymptomatic cryptococcal anti- Chronic obstructive pulmonary disease (COPD) rep- genaemia combined with pre-emptive antifungal therapy resents an important, nonclassical underlying condition with fluconazole has proven to be an effective strategy for the increasing number of acute invasive pulmonary to prevent symptomatic meningitis whilst reducing the aspergillosis, with a very high mortality rate. Associated number of deaths.(43) Nevertheless, worldwide there are with the pulmonary disease, structural modifications in circa 225,000 estimated new cases of cryptococcal men- the lung architecture that favour lung parenchyma inva- ingitis per year, causing over 180,000 deaths, which ac- sion and necrosis due to Aspergillus spp., in addition to counts for about 15% of AIDS-associated deaths.(44) In prolonged use of immunosuppressive treatment, such as addition, concomitant treatment with antiretroviral drugs therapy, might increase the susceptibil- in patients with AIDS-related cryptococcosis can cause ity of COPD patients to acquire an IFD.(54) Furthermore, exaggerated inflammatory response as a result of im- recurrent hospitalisation, invasive procedures, broad- mune reconstitution inflammatory syndrome, which spectrum antibiotic use and other factors such as tobac- contributes to even higher mortality rates.(40,45) co smoke, alcoholism, diabetes mellitus and/or malnutri- Histoplasmosis and , caused by the tion could contribute to promote invasive aspergillosis in thermal dimorphic fungi Histoplasma capsulatum (E in COPD patients.(54,55) Figure) and Talaromyces (formerly Penicillium) marnef- Bacterial and viral co-infections fei, respectively, are also major opportunistic infections affecting patients with HIV/AIDS, which present mostly Fungal pulmonary infections can be acquired primar- as disseminated disease.(42) Disseminated histoplasmo- ily or secondarily during tuberculosis infection. Co-mor- sis, reported worldwide with about 100,000 cases occur- bidities such as immunodeficiency, mainly due to HIV, ring every year, has most endemic cases in the Americas, chronic illnesses and malignancy, together with inherent where the incidence has been estimated to reach 25% of factors of the community like poverty and malnutrition, patients with HIV infection, being an AIDS-defining ill- worsen the co-infection and the prognosis of patients.(56) ness in up to 75% of patients and with mortality rates of In 2018, it was estimated that globally 10 million people almost 60%.(6,42,46) In Latin America, it is estimated that, contracted tuberculosis, causing 1.2 million deaths among among people living with HIV, the number of deaths HIV-negative people and 251,000 deaths associated with caused by histoplasmosis may be higher than those HIV infection.(57) As fungal pulmonary disease does not caused by tuberculosis. In fact, histoplasmosis, which show specific radiological and clinical manifestations, is considered neglected in this region, is often misdi- compared to those of pulmonary tuberculosis, misdiagno- agnosed as tuberculosis(47) Talaromycosis, restricted to sis and late or no-antifungal therapy cause high morbidity southeast Asia, southern China and northeastern India, and mortality rates in co-infected patients. With an inci- remains one of the major causes of HIV-associated mor- dence that can reach 50% of cases, depending on the geo- tality in these endemic areas, especially in people with graphical distribution, different fungal pathogens coexist undiagnosed and untreated HIV infection.(42,46,48) with pulmonary tuberculosis, amplifying the severity of Uncontrolled diabetes mellitus, particularly in pa- the disease, especially when dissemination occurs. A. fu- tients having ketoacidosis, is the major predisposing fac- migatus, Aspergillus niger, H. capsulatum, C. neoformans tor for developing mucormycosis, which is the third most and C. albicans are often responsible for causing severe common angioinvasive fungal infection following can- secondary infections in tuberculosis patients.(10,56,58,59) 6|9 Carolina Firacative

Reactivation of latent cytomegalovirus (CMV) can patients with strong haemorrhage and/or receiving blood lead to the development of concomitant or sequential fun- transfusions.(52) Mucormycetes have been reported caus- gal infections in immunosuppressed patients. Both solid ing outbreaks of traumatic implantation of contaminated organ and autologous stem cell transplant recipients, with soil or water after natural disasters, including tsunamis a history of CMV infection, have higher risk for devel- and tornadoes. Motor vehicle collisions and blasts from oping IFD.(60,61) In HSCT patients, Pneumocystis pneu- war-related injuries are also common forms to get se- monia and invasive mold infections, including invasive vere trauma among the population.(71) After dissemina- aspergillosis, represent the most commonly encountered tion occurs, even young, previously healthy patients are IFD during the late post-engraftment period.(32,61) Un- susceptible to mucormycosis and even with aggressive treated CMV viremia, which occurs primarily in patients approaches such as disfiguring debridement or amputa- who were seropositive before transplantation and who tion, case-fatality rate can reach 100%.(71,72) develop GvHD, is followed by pneumonia that may be accompanied by superinfection with fungal pathogens, In conclusion, concomitant with the increased leading to substantial morbidity and mortality.(30) prevalence of at-risk and immunocompromised people, A dysfunctional immune response, which can cause rates and spectrum of invasive fungal infections are ris- severe alveolar lung damage and even systemic pathol- ing and becoming more frequent worldwide. Certainly, ogy, has been reported to occur rarely in people with opportunities are increasing for opportunistic fungi. coronavirus disease 2019 (COVID-19), a viral infec- Extended survival of patients related to improvements tion caused by the severe acute respiratory syndrome in supportive and intensive care, prolonged treatment coronavirus 2 (SARS-CoV-2), first reported in Wu- of bacterial infections, high-dose chemotherapeutic han, China, at the end of 2019.(62,63) While unusual, this regimens to treat , global practice of solid organ harmful interaction of SARS-CoV-2 with the immune and stem cell transplantation procedures, increased use system of patients with severe COVID-19 pneumonia of immunosuppressive and biologic therapies, the ad- seems to increase the susceptibility of these patients to vent of AIDS, and even natural disasters, among other acquire secondary infections, including certain myco- factors, significantly contribute to the impact of fun- ses.(62) Although the incidence of IFD associated with gal pathogens on human health. Although advances in COVID-19 is still unknown, Aspergillus infections medical technology, improved diagnostics, earlier ad- have been, so far, the most commonly reported fungal ministration of antifungal treatments and more effec- co-infections in COVID-19 patients.(64) Invasive asper- tive preemptive therapy have helped reducing morbidity gillosis, however, has been associated with admission and mortality for most IFD, fungal opportunistic infec- to critical care because of COVID-19 pneumonia and tions persist severe, often underdiagnosed, life-threat- severe acute respiratory syndrome.(65) In addition, most ening and have a significant economic burden. There- co-infected patients had previous history of underlying fore, as fungi are ubiquitous in the environment and immunocompromised status or pre-existing comorbid- they are increasingly infecting vulnerable populations ities, mainly hypertension, diabetes, obesity and hae- worldwide, especially those living in resource-limited matological malignancies.(65,66) Much less frequently, settings, there is an urgent need to increase clinical candidiasis has been also reported as co-infection in awareness, in order to develop early intervention strat- hospitalised patients with COVID-19.(67,68,69) However, egies. Identifying major risk factors or conditions is of the contribution of the underlying disease and CO- utmost importance to prevent IFD and meet the need VID-19, as attributable risk factors to acquire fungal of decreasing the still staggering high mortality-asso- infections requires careful analysis and to date remains ciated rates. Moreover, even though IFD are among the to be determined.(64) deadliest communicable diseases worldwide, the vast majority of these mycoses are not reportable to public Environmental exposure health authorities in most countries, which represents Environmental factors play a unique role in the epi- another challenge and makes IFD less likely to be doc- demiology of invasive mold infections. Although infre- umented. Whilst waiting for mandatory case reporting, quent, these opportunistic infections are serious compli- comprehensive eco-epidemiological studies together cations of both traumatic and post-traumatic injury.(70) with voluntary reports from clinicians and laboratories Patients can be directly inoculated during tissue injury; are needed, aimed to improve disease surveillance and alternatively, fungi can infect the tissue after skin trau- to achieve a better understanding of the public health ma, burns or surgery. In all patients, however, cutaneous implications of IFD around the world. Obtaining a true manifestations are followed by angioinvasion, which re- picture of the global burden of invasive mycoses, in- sults in vessel thrombosis and tissue necrosis.(53) When cluding the patients’ associated conditions and risk fac- the patient has any kind of immunosuppression besides tors, is key to making decisions and providing inputs the traumatic injury, tissue infarction and necrosis occur into health-care services, programmes, responses and usually shortly after the inoculation event.(70) Globally, policies, which will ultimately be addressed to improv- mucormycosis is the most common fatal complication ing people’s health and wellbeing. that can occur after trauma, because of the quick dis- semination of spores and deep extension to bone, tendon, ACKNOWLEDGEMENTS or muscle, after skin disruption.(51) Upon inoculation, R. To Dr Elizabeth Castañeda and Dr Simon Dingsdag, for oryzae obtains iron from the host, which is abundant in their valuable suggestions during the writing of the manuscript. Mem Inst Oswaldo Cruz, Rio de Janeiro, Vol. 115, 2020 7|9

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